1. Field of the Invention
This invention relates to an orally administered antibody with respiratory syncytial virus (RSV), adenovirus, parainfluenza virus, or influenza virus neutralization activity and its use to decrease the incidence or severity of RSV or other viral infections of the upper and lower respiratory tract.
2. Description of the Prior Art
Respiratory syncytial virus is the major cause of pneumonia and bronchiolitis in infancy. Infants between the ages of two and five months have the most severe disease and may require hospitalization. More than half of all infants become infected with RSV during their first year of exposure, and nearly all are infected after a second year. Children who attend day care centers tend to have more severe infections and at an earlier age. Repeated RSV infections are common, although repeat episodes tend to be less severe.
During seasonal epidemics most infants, children, and adults are at risk for infection or reinfection. In addition to infections in healthy infants and children, other groups at risk for serious RSV infections include premature infants, hospitalized children, infants and children with cardiac or pulmonary disorders, immune compromised children and adults, and the elderly. Symptoms of RSV infection range from a mild cold to severe bronchiolitis and pneumonia. Respiratory syncytial virus has also been associated with acute otitis media and RSV can be recovered from middle ear fluid.
Respiratory syncytial virus is an RNA virus that can produce cell fusion (syncytia) in tissue culture. It is classified as a pneumovirus within the paramyxovirus family. The RNA genome codes for at least 10 proteins including two matrix proteins in the viral envelope (Ryan, Sherris' Medical Microbiology, 3d ed., Appleton and Lange, p. 458, 1994). One matrix protein forms the inner lining of the viral envelope. Antigens on the surface of the envelope are the G glycoprotein, the probable attachment site to host cell receptors, and the F glycoprotein that induces fusion. G glycoprotein antibodies can neutralize the virus in vitro.
Infection with the virus causes both IgG and IgA humoral and secretory antibody responses. Immunity is not permanent and repeated infections are common, however the severity of illness tends to diminish with increasing age and with successive reinfection. No vaccine has been shown to be protective against RSV and antiviral drugs have so far had only limited utility. Breast feeding may offer some protection against RSV infection. RSV-specific IgA and IgG antibodies have been found in human milk and colostrum and RSV neutralization can be accomplished in cell culture with both immunoglobulin and non-immunoglobulin components of human milk (Laegreid et al., "Neutralizing Activity in Human Milk Fractions against Respiratory Syncytial Virus, Acta Paediatrica Scandinavica, 75:696-701, 1986).
Okamato et al., (Acta Paediatrica Scandinavica Supplement, 351:137-143, 1989) report that immunity acquired by an infant either through the placenta or through breast feeding may reduce the risk of lower respiratory tract disease. The focus of the report of Okamato et al. is on the role of maternal antibodies transmitted in breast milk and the possible role of breast milk in modulating an infant's immune response to RSV. The focus of the instant invention is on a method of producing passive immunity by adding neutralizing antibodies to a product that will be orally ingested. Orally ingested as used herein refers to a substance that is swallowed by the host.
Previous treatments for infection by RSV have relied upon either parenteral or aerosol administration of agents such as monoclonal antibodies or viricidal drugs such as ribavirin. The present invention discloses oral administration of an antibody with RSV neutralizing activity.
Prince et al. (U.S. Pat. No. 4,800,078) teach a method for topical application of antibodies to RSV into the lower respiratory tract, preferably by administering immunoglobulins as small particle aerosol. The immunoglobulins can also be administered by the intravenous route.
In U.S. Pat. No.5,290,540, Prince et al. disclose topical administration in the form of small particle aerosol of both an anti-inflammatory agent and an anti-infectious agent in the treatment of pneumonia caused by bacteria or viruses including RSV.
CA 2,040,770 to Young et al. discloses a process for the treatment of respiratory viruses, including RSV, by administering a neutralizing or non-neutralizing monoclonal antibody against a fusion protein of RSV (the F glycoprotein). Monoclonal antibody treatment using the method of Young et al. may be topical and administered intranasally or by breathing an aerosol, or systemic by intramuscular administration. The present invention, by contrast, discloses an orally administered treatment.
WO 92/01473 discloses the treatment of lower respiratory tract viral disease using the small particle aerosol method to deliver neutralizing and/or therapeutic monoclonal antibodies to specific viral surface antigenic sites.
WO 92/19244 teaches the combination of an anti-infective agent such as human immunoglobulin G or an antibiotic combined with an anti-inflammatory agent or corticosteroid delivered into the respiratory tract in the form of small particle aerosol.
WO 94/17105 discloses human-murine chimeric antibodies with high specific neutralizing activity against RSV, preferably against the RSV F antigen.
The prior art references disclose delivery of a virus neutralizing compound either topically by inhalation of a small particle aerosol or parenterally by intravenous or intramuscular injection. Feeding a non-absorbed RSV neutralizing compound to prevent or decrease the incidence and severity of RSV infection has not been disclosed or demonstrated in the prior art references. This concept, as demonstrated in the present invention, depends on the ability of an RSV neutralizing antibody to decrease the viral load on mucosal surfaces of the nasopharynx, oropharynx, and hypopharynx, and thereby prevent or decrease the spread of infectious virus from nose to lung when the antibody is swallowed. Delivery of an RSV neutralizing antibody in a liquid product is particularly advantageous because of the ease of administration.